Benefit of Adjuvant Mesenchymal Stem Cell Transplantation to Critical-Sized Peripheral Nerve Defect Repair: A Systematic Review and Meta-Analysis of Preclinical Studies

Round 1

Reviewer 1 Report

This is an article that compares data previous published on the benefit of adjuvant MSCs transplantation to critical size nerve defect repairs. This comparison may be of some interest to summarize the effectiveness of this type of treatment.

As a review article, the introduction should be more developed.

In the discussion, you should highlight and compare in more depth the differences found in the control groups (without MSCs) and the study groups (with MSCs) in order to be able to predict on the positive effect of the treatment with the MSCs.

Discussion should also address the influence of different types of MSCs (Xenograftes / autograft) and their origins (bone marrow, adipose, dental pulp, umbical cord and skin), as well as the different types of nerve defect bridging. (This comparison should be done carefully, in generic terms, as different studies cannot be compared mathematically).

In the conclusions you should add what is the most consensual therapeutic option (based on data obtained from this bibliographical research) for the treatment critical size nerve defect repairs, especially with regard to the different types of MSCs (Xenograftes / autograft) and their origins (bone marrow, adipose, dental pulp, umbical cord and skin).

Author Response

Please see attached file.

Author Response File: Author Response.docx

Reviewer 2 Report

Thank you for your work on summarizing the knowledge on MSC use in PNI. Especially the fact that you performed a systematic review with metanalysis of pivotal parameters assessed in PNI preclinical studies. Overall, study was conducted properly with the use of appropriate tools (risk of bias tool, Cochrane review manager etc.)

Yet, in my opinion, some issues should be discussed more thoroughly:

1) 2.1 - please specify the exact timeframe of your search engine - both start and finish date of published articles included in your analysis. 

2) Table 1. - please explain the 1,5 mm cutoff for the inclusion criteria. It is a matter of controversy what is the size of the defect in peripheral model in preclinical setting. Most of the that examines PNI management, also with the aid of a conduit applies 10mm gaps (e.g. see https://doi.org/10.1016%2Fj.biomaterials.2012.07.056). Thus, please justify the limitation you implanted, with the use of appropriate literature. Also, you should highlight that fact in the limitations of the study and even abstract. Otherwise, the study should be expand its inclusion criteria.

3) 3.2 - risk of bias assessment. Please provide the figure depicting individual results of your assessment with SYRCLE's tool. You redirect the readers to figure 3 but the figure contains the forest plot of MSC influence on nerve conduction velocity. Yet, summary of risk of bias quality was performed properly.

4) Have you performed any sensitivity analysis for particular subgroups analysis in any parameter?

5) In included studies, in the control groups, if you had one, how you managed a situation when there was more than one control group e.g. block resection of the nerve and defect treated with blank conduit (no-MSC)? 

6) in my opinion the discussion is slightly too general ale not concise. Rather than description of general issues of PNI and MSC properties authors should focus on discussing the results of their analysis in context of literature and strength of MSC based therapies in PNI vs other methods or specific conduit types.

7) in my opinion qualitative analysis of included works would also improve the manuscript, but if it make the manuscript too length it is understandable to publish it in separate paper or as a significant supplement

8) In limitations or any other part of manuscript there was no mention about the composition of their types in included studies - which I supposed varied (line 99-100). Also, the type of a conduit may have affected the result and a sensitivity analysis or subgroup analysis in that context could be insightful. Please expand discussion on that matter.

Author Response

Please find attached file 

Author Response File: Author Response.docx

Reviewer 3 Report

1. Fig.1- Studied excluded

2.  the exclusion by title and abstract screening is done twice? the 1st one supposed to be duplication removal

3. Line 104-105 (25 studies included in qualitative synthesis; 22 studies included 104 in quantitative synthesis) don't correlate with Fig 1

4. Line 141-142 - muscles are controlled and nourished by the sciatic nerve- Do muscles nourished by nerves?

5.  A table summarising the injury model, type of conduit, defect site, MSC type, observation period, etc should be included.

6. The word adjuvant in title refer to what? MSC act as adjuvant of what? This wasn't explained in the paper.

7. Overall, the discussion parts can be expanded to better compare and analyse the results, especially on the parameters from various studies, that were compared in the Result section. 

8. The mechanism of action of MSC, according to the original articles can also be summarised here to give a better understanding of the MSCs role and action in nerve injury repair. The Intro also can be expanded with more basic explanation on nerve injury and repair to give a better understanding to the wider audience of this journal

9. The role of MSC in promoting tumour seems to be selectively discussed, in my opinion. I expect for a more balanced discussion on this. 

Author Response

Please find attached file 

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Thank you for the response and changes made to the manuscript.

Now some aspects of your study are more clear. Yet I would suggest to incorporate some statements in the main text, namely:

 Please add the main point of controversies in critical gap size in preclinical research of PNI and clearly highlight on what literature basis you chose to limit the study to at least 15mm gap (as you did in the response). The paragraph should be added in methods section, near the inclusion criteria table. Also, in the paragraph on study limitation you should mention the fact that most of the studies relied on a rat model and you discarded numerous studies with smaller size gap

2) It is rather a question than request. Have you performed an analysis of subgroups based on different conduit type, especially synthetic vs tissue-derived one? I know that low number of studies hamper elucidating conclusions on that, but indicating which of those two performed better with MSC could pose a useful roadsign for further research. 

Also, corrections should be made in figures 4-8 - interpretation of the results should be inverted. 

Author Response

We thank the reviewer and the editorial board members for their fast response to our revisions and the valuable additional input we received from your side.

Please find below a list of the changes we undertook in order of the points in the review.

 

1. We thank the reviewer for this suggestion and have added a paragraph explaining our choice for gap size in the methods section of the manuscript and explained it in depth in the discussion section.
   We have also added the recommended section to our limitations.
2. We did not perform this sub-analysis. We decided against doing so after considering the inhomogeneity in these subgroups, due to the highly different properties of different synthetic and biological conduit materials, and the relatively low number of included studies after splitting them up into further categories as well.
3. Thank you, we have changed the image descriptions.